Switchable Lipids: From Conformational Switch to Macroscopic Changes in Lipid Vesicles.

Area of Science:

• Biochemistry
• Materials Science
• Nanotechnology

Background:

• Conformationally pH-switchable lipids improve cytosolic drug delivery via lipid vesicles.
• Understanding pH-triggered cargo release mechanisms is key for designing effective pH-switchable lipids.

Purpose of the Study:

• To elucidate the mechanism of pH-triggered membrane destabilization and cargo release from lipid nanoparticles.
• To investigate how pH-switchable lipids influence lipid nanoparticle assembly and membrane properties.

Main Methods:

• Morphological analysis (FF-SEM, Cryo-TEM, AFM, confocal microscopy).
• Physicochemical characterization (DLS, ELS).
• Phase behavior studies (DSC, 2H NMR, Langmuir isotherm, MAS NMR).

Main Results:

• pH-switchable lipids incorporate into lipid nanoparticles, promoting a stable liquid-ordered phase.
• Acidification protonates switchable lipids, altering self-assembly and causing membrane fluctuations and local defects.
• These membrane defects, not phase separation, enhance permeability and trigger cargo release.

Conclusions:

• pH-triggered release is mediated by subtle membrane defects induced by pH-switchable lipids.
• Rational design of pH-switchable lipids can be optimized by understanding their impact on membrane permeability.
• This mechanism allows for cargo release without significant morphological changes in lipid vesicles.